(a) Field
The subject matter disclosed generally relates to modulators of Nrf2, and more specifically to compounds which binds at least one of the BTB domain, IVR domain and Kelch domain of Keap1 protein, activating or inhibiting Nrf2.
(b) Related Prior Art
As chemical carcinogenesis likely plays a role in cancer development, cytoprotective enzyme induction is believed to be an important means of cancer chemoprevention. Transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) regulates a battery of genes encoding carcinogen-detoxifying enzymes and antioxidant proteins by binding to the antioxidant response element (ARE) promoter regulatory sequence. Under basal conditions, in which the redox homeostasis is maintained in cells, Nrf2 is sequestered in the cytoplasm by a protein known as Keap1, which targets Nrf2 for ubiquitination and degradation by the proteasome, and thus controls both the subcellular localization and steady-state levels of Nrf2. In response to oxidative stress or chemopreventive compounds, Keap1-mediated ubiquitination of Nrf2 is decreased significantly and the Nrf2 pathway is turned on. Thus, Keap1 is a molecular switch that senses various stimuli and turns the Nrf2 pathway on and off. Administration of Nrf2-inducing agents has been shown to result in decreased carcinogenesis in animal models and altered carcinogen metabolism in humans. Clinical interventions have shown that Nrf2 inducers increase cytoprotective enzyme expression, resulting in modulation of aflatoxin disposition.
Interestingly, Nrf2 and its downstream genes are overexpressed in many cancer cell lines and human cancer tissues, giving cancer cells an advantage for survival and growth. Furthermore, Nrf2 is upregulated in resistant cancer cells and is thought to be responsible for acquired chemoresistance. Therefore, it may be necessary to inhibit the Nrf2 pathway during chemotherapy, and thereby favor the action of concomitantly administered chemotherapeutic agents.
Keap1 contains the BTB domain mediating Keap1 homodimer formation, the ‘intervening region’ (IVR) (amino acids 180-314), and the C-terminal Kelch domain that mediates binding to the Neh2 domain of Nrf2. Human Keap1 contains 27 cysteine residues. Three key cysteine residues (C151, C273, and C288) have been identified. C151 is required for several Nrf2 inducers, such as sulforaphane (SFN) and tert-butylhydroquinone, to manifest their effect. Importantly, residues C273 and C288 at the IVR domain are necessary for Keap1 to repress Nrf2. A single cysteine to serine mutation C273S or C288S render Keap1 unable to repress Nrf2. The transgenic expression of mutant Keap1(C273A) and/or Keap1(C288A) protein in Keap1 null mice failed to reverse constitutive Nrf2 activation, indicating that cysteine residues at positions 273 and 288 are essential for Keap1 to repress Nrf2 activity in vivo. This suggests a critical role of the domains of Keap1 in the regulation of the functional interaction of Keap1 with Nrf2.
Therefore, there is a need for the identification of small molecules to modulate the interaction of Keap1 with Nrf2.
There is a need for the identification of small molecules to induce Nrf2 activity and stimulate or at least positively influence its activity.
There is a need for the identification of small molecules to inhibit Nrf2 activity and prevent or at least negatively influence its activity.